Danazol, sold as Danocrine and other brand names, is a medication used in the treatment of endometriosis, fibrocystic breast disease, hereditary angioedema and other conditions. It is taken by mouth.
The use of danazol is limited by masculinizing side effects such as acne, excessive hair growth, and voice deepening. Danazol has a complex mechanism of action, and is characterized as a weak androgen and anabolic steroid, a weak progestogen, a weak antigonadotropin, a weak steroidogenesis inhibitor, and a functional antiestrogen.
Danazol was discovered in 1963 and was introduced for medical use in 1971. Due to their improved side-effect profiles, particularly their lack of masculinizing side effects, danazol has largely been replaced by gonadotropin-releasing hormone analogues (GnRH analogues) in the treatment of endometriosis.
Medical uses
Danazol is used primarily in the treatment of endometriosis. It has also been used – mostly off-label – for other indications, namely in the management of menorrhagia, fibrocystic breast disease, immune thrombocytopenic purpura, premenstrual syndrome, breast pain, and hereditary angioedema. Although not currently a standard treatment for menorrhagia, danazol demonstrated significant relief in young women with menorrhagia in a study, and, because of a lack of a significant adverse effects, it was proposed as an alternative treatment. Danazol appears to be useful in the treatment of systemic lupus erythematosus.
Available forms
Danazol comes in the form of 50, 100, and 200 mg oral capsules. It is taken at a dose of 50 to 400 mg two or three times per day, for a total of 100 to 800 mg per day depending on the indication.
Contraindications
Danazol is contraindicated during pregnancy because it has the potential to virilize female fetuses. Women taking danazol should practice effective contraception to prevent pregnancy if sexually active.
Since danazol is metabolized by the liver, it cannot be used by patients with liver disease, and in patients receiving long-term therapy, liver function must be monitored on a periodic basis.
Side effects
Androgenic side effects are of concern, as some women taking danazol may experience unwanted hair growth (hirsutism), acne, irreversible deepening of the voice, or adverse blood lipid profiles. In addition, breast atrophy and decreased breast size may occur. The drug may also cause hot flashes, elevation of liver enzymes, and mood changes.
The use of danazol for endometriosis has been linked to an increased risk of ovarian cancer. Patients with endometriosis have specific risk factors for ovarian cancer, so this may not apply for other uses. Danazol, like most other anabolic steroids, has been linked with an increased risk of liver tumors. These are generally benign.
Pharmacology
Pharmacodynamics
Danazol possesses a complex pharmacology, with multiple mechanisms of action. These include direct binding to and activation of sex hormone receptors, direct inhibition of enzymes involved in steroidogenesis, and direct binding to and occupation of steroid hormone carrier proteins and consequent displacement of steroid hormones from these proteins. The drug is characterized as a weak androgen and anabolic, a weak progestogen, a weak antigonadotropin, a weak steroidogenesis inhibitor, and a functional antiestrogen.
Modulation of steroid hormone receptors
Danazol is described as a possessing high affinity for the androgen receptor (AR), moderate affinity for the progesterone receptor (PR) and glucocorticoid receptor (GR), and poor affinity for the estrogen receptor (ER). As an androgen, danazol is described as weak, being about 200-fold less potent than testosterone in bioassays. The drug can act as both an agonist and antagonist of the PR depending on the bioassay, indicating that it could be regarded as a selective progesterone receptor modulator (SPRM). Although the affinity and efficacy of danazol itself at the PR are relatively low, ethisterone, one of the major metabolites of danazol, is described as a weak progestogen (and has been employed clinically as a progestogen), and this presumably serves to increase the in vivo progestogenic activity of danazol. The activity of danazol at the ER is considered to be minimal, although at very high concentrations the drug can act significantly as an ER agonist. Danazol is considered to act significantly as an agonist of the GR, and, thus, as a glucocorticoid. In accordance, it can suppress the immune system at sufficient dosages.